2-(4-succinyl-amino-benzenesulphonamido)-quinoxaline



Patented July 16, 1946 AMINO-BENZENE- 2- l-SUCCINYL- SULPHONAMIDO)-QUINO XALINE John Weijlard, Westfield, and Max Tishler, Rah

way, N. J assignors to Merck & 00.,

Inc., Rahway, N. J a corporation of New Jersey No Drawing.

This invention, in its more general aspects, relates to therapeuticallyuseful chemical compounds and methods of preparing the same; morespecifically, it is concerned with certain novel :ulpha drugs andprocesses for their manufacure.

This application is a continuation-in-part of a copending applicationfiled by the same applicants on January 8, 1944, Serial No. 517,560,entitled chemical compounds and processes of preparing the same.

Although it is possible for a skilled chemist, knowing certain physicalpropertiesand the behavior of a substance toward various chemicalreagents, to predict with reasonable accuracy corresponding physicalproperties and probable chemical reactivity of substances, such ashomologs, related to the known compound, it is not. generally possiblefor even an experienced worker to predict the physiological activity ofchemical compounds. For example, certain of the vitamins are highlyspecific in physiological activity and changes in molecular structurethat produce little difference in physical properties or chemicalreactivity cause extreme differences in physiological activity. Invitamin B1, when the amino-group of the amino-pyrimidine moiety isreplaced by a hydroxyl group, the characteristic physiological activityis destroyed; dihydro-vitamin B1 is inactive althoughdihydro-cocarboxylase is active. When in vitamin 131, the methyl groupoccupying the 2-position in the pyrimidine moiety is shifted to the6-position the second compound possesses but a small fraction of theactivity of the first. Vitamin B2, riboflavin, when alkylated in the3-position, loses entirely its characteristic activity. Vitamin B6benzoate is inactive although the diand tri-acetate' of the Vitamin arefully active; the methyl-ether of the vitamin possesses but /500 of theactivity of the vitamin. Dextro-rotatory arltothenic acid is fullyactive: the laevorotatory isomer is inactive. The acetate, benzoate anddiphosphate of pantothenic acid are inactive. Dihydro-ascorbic acid isinactive; dehydro-ascorbic acid is fully active.

Following the discovery of the remarkable bacteriostatic properties ofp-amino-benzene-sulphonamide, various related compounds have been testedas therapeutic agents and it has been found that certain are valuable intreating specific diseases. For example sulphanilamide is particularlyuseful in treating conditions due to hemolytic streptococcic infections;sulphapyridine in treating peneumonia and, gonorrhea; sulphathiazole andsulphadiazine in treating pneumonia, gonorrhea, E. coli andstaphylococcic infections; sulphaguanidine in bacillary dysentery; andsuccinylsulphathiazole in treating diseases limitedtothegastro-intestinal tract. However, because of the impossibility ofpredicting Application September '7, 1944, 7 Serial No. 553,10 1 1 1Claim. (01. 260-2395) 2 activity of a particular the basis of knownactivity of a physiological merely upon related or, similar compound, ithas been necessary, in developing new sulpha compounds, to test invivo"the chemical substance concerned;

It is noteworthy, in this connection, that certain sulpha-monocycliccompounds display highactivity although corresponding sulpha-bicycliccompounds are merely slightly active. For instance, sulphathiazole(Formula A) islhighly active as above mentioned, but sulphabenzothiazole(Formula B) has only slight'bacteriostatic activity; likewisesulphapy'ridine (Formula C) is active but sulphaquinoline (Formula D) isrelatively inactive. Formula A 0 a g g H,N S-NC .CH H I 0 H N FormulaB vi i-i l v HzN s-rr-o o on 1 s ll l .o-H N 0 FormulaC (R Q N n iu 0 H sFormulaD N i'i O H M It is now found by the present inventors that a newsulpha-compound, 2-(4-amino-benzene-' sulphonamide)-quinoxaline, havingthe struc-' tural formula possesses valuable and unusual therapeutic,11011,. ity, -It is remarkable and unexpectedin view of the relativeinactivity of the bicyclic sulpha compounds above mentioned, that thisnew material is physiologically more active than its monocyclic analog,2'-(4-amino benaene-sulphonamido) -pyrazine'f Another remarkable'andunpree dictable property of this new substance is that it is lessr'apidl y excretedby the organism under treatmntthan are otherslpha-compounds, thus in the treatment of pneumococcic, 'staphylococcicand "similar infections, a satisfactory bacteriostatic' concentration ofthe-compound can be maintained using a lower rate of administrationcompound be administered at intervals A mare of about "and; afterstanding, the distillation-and Water is do) -.quin oxaline,

than is re ui d w th t r sulph -druss- F r example, an adequate bloodlevel of the new compound is attained when it is administered atintervals of twenty-four to forty-eight hours, whereas othersulpha-drugs, in the same dosage, must' of four to six hours to maintaincorresponding levels.

In accordance with the present invention, this new compound can besynthesized byreflfitions indicated as follows: a 1

TN Hz cozH The following example illustrates a method of l0 carrying outthe present invention, but 1t is to be understood that this example isgiven by way of I illustration and not'of limitation. I

v EXAMPLE Synthesis of Z-amino-3-carboa:y-quinoa:aline About g. ofalloxazine (Ben, 24, 2363 (1891) 1 are'mixed with approximately 50 cc.of concen- 1 trated ammonia and heated in a bomb at 165 C. 1 for about10 hours. After dilution with water and 1 removal of ammonia by boiling,decolorizin with J charcoaland filtering, hydrochloric acid is addeduntil the 'mixtureis of pH 2.5. Upon cooling, 2-

, t N t 65 Synthesis of Z-amz'noqwinozaline About 2 g. of2-amino-3-carboxy-quinoxaline are dissolved in'about 8 cc. of hotnitrobenzene and the solution is refluxed for 10 minutes, then cooledand diluted with approximately cc. of

petroleumpether, v'lh du t, 2-am n u n- 'oxafinaseparates as r stals P.15 -1 1 Q). ynthesis of 2=(4-acet laminotamenfisubhont amide) pan omimeg. of 2,-amin0-quinoxaline g. of p-acetylaminovben zene-sulphonylchloride are added in small portions with'agit'ation to about cc. ofcold (3- T; 0,.) pyridine. The mixture is stirred with cool, inthenheated at id-50 C. for about 2 hours pyridine is removed by added totheresidue. The: product, 2-:(4-amino-benzene-sulphonamiis obtained ascrystals that can and approximately 8.8

j perature of -.90

4 e purified by re rystal ization from dilute a c acid (M. P. 244.5-2450,); By substituting pbenzoylamino-benzene-sulp-honyl chloride orpcaproylamino-benzene-sulphonyl chloride for the'p-acetylamino-benzene-sulphonyl chloride in the last re ction, 2-l-benzoylamino-benzene-sulphonamido)-quinoxaline (M. P. 259-260 C.) or2- (4-caproylamino-benzene-sulphonamido) quinoxalineiM, 1?.- -152" C.,initially, 199200 C. after solidification and remelting) respectively Hcan be obtained. Synthesis of '2 (4 amino-benzene-sulphonamido)-qumoxaline About 6 g. of crudeZ-(Q-acetylamino-benZenesulphonamido)-quinoxaline, 50 cc. of ethanol and25 cc. of concentrated hydrochloric -acid are refluxed for about anhour, thendil'uted with water; treated with ammonium hydroxide 'to'slight alkalinity and'with' acetic acid to slight acidity. After coolingthe crystals formeda're" collected, dissolved in about 50 cc. of sodiumhydroxidesolution, treated with activated charcoal, filtered, and-thesolution is slightly acidified. The product, 2-(4'-amino-'benzene-'sul'phonamidm-quinoxaline, is obtained as crystals 7 (M. P. 2495-250 0.).

The'benzoyl or' caproyl compounds can also be hydrolyzed by' this acidtreatment to give 'the'sam'e product or, if pre-"i these acyl de-'ferred, the hydrolysis of' any of rivatives can be performed under basicconditions using manner."

phonamido) -guinogcalin,e

About'15 g. (0.15 mol)' of succinyl 'anhydride and approximately 30 g;(0.10 mol) of 2+(4-amino-benzene-sulphonamido) solved in about 200 cc.of dry pyridine-at a tem 0;, and the solutionisheated at thistemperature for approximately 2 'hours. After standingat tion is dilutedwith about a liter ofwater and 250 cc. of glacial acetic acid are added,causing separation of the product, benzene-rsulphonamido) -q'uinoxaline,

I V (C1sH eO15N4) .7 l. as crystals having a melting point of 234-235 C;which are fully soluble in alkaline aqueous solutions. w Modificationsmay be made in carrying'out the present invention without departing fromthe spirit and scope thereof and the invention is to be limited only bythe appended claim.

What is claimed is: A compound representedby the formulai wherein R is asuccinyl group? I JOHN iWEIJLARnI aqueous alkali' solutions in" the"usual -quinox'aline are disroom temperature; the 'solu 2- (4-'-succinylamino-

